Preoperatory treatment of adenocarcinoma of the rectum: historical analysis and correlation between tumor regression grade and the outcomes

ABSTRACT

Introduction: Treatment of locally advanced rectal cancer is based on chemoradiation associated with surgery. Tumor regression grade (TRG) appears to be a prognostic factor and be influenced by the interval between neoadjuvant treatment and surgery.

Material and Methods: A retrospective database was formed. We included patients submitted to neoadjuvant chemoradiotherapy and rectal surgery, treated at the Hospital de Clínicas, Porto Alegre. TRG was mensurated by the modified Ryan method, as the American Joint Committee on Cancer (AJCC) suggests. We analyzed outcomes, pathological tumor regression and treatment toxicity data. We also sought to analyze the optimal timing for surgery after chemoradiotherapy, comparing different intervals after chemoradiotherapy with the rate of pCR. Statistical analysis was done with Kaplan Meier, Pearson's chi-square, and the Cox regression method.

Results: We accrued 156 patients between 2006 and 2018. The rate of DFS at 3 and 5 years were 75% and 70%, respectively. The 5-year overall survival was 88%. The rate of pCR was 12.8%. TRG 3 was associated with an increase in mortality, HR 3,148 (95%CI: 1.6-12.2, p<0.003) and a decrease in DFS, HR 3,148 (95%CI: 1.7-5.8, p<0.0001). The 5-years DFS with TRG 0,1, 2 and 3 were 95%, 87%, 73.3%, and 48%, respectively. Comparing the interval between the end of radiotherapy treatment and surgery of less than 8 weeks versus 8 and 12 weeks versus above 12 weeks, the rates of pCR were 4.3%, 18.6% and 7.1% and the rates of TRG 3 were 32.6%, 18.6%, and 57,1% (p<0.016), respectively.

Conclusion: The outcomes found are favorable. The pathological tumor regression grade is an important prognostic factor. The interval between the neoadjuvant treatment and surgery seems to influence the tumor regression grade, with the best results of surgery observed when performed between 8 and 12 weeks.

RESUMO

Introdução: O tratamento do câncer retal localmente avançado é baseado na quimiorradiação associada à cirurgia. O grau de regressão tumoral (TRG) parece ser um fator prognóstico e é influenciado pelo intervalo entre o tratamento neoadjuvante e a cirurgia.

Material e Métodos: Um banco de dados retrospectivo foi formado. Foram incluídos pacientes submetidos à quimiorradioterapia neoadjuvante e cirurgia retal, atendidos no Hospital de Clínicas de Porto Alegre. O TRG foi mensurado pelo método de Ryan modificado, como sugere o American Joint Committee on Cancer (AJCC). Analisamos os resultados, a regressão patológica do tumor e os dados de toxicidade do tratamento. Também procuramos analisar o momento ideal para a cirurgia após a quimiorradioterapia, comparando diferentes intervalos após a quimiorradioterapia com a taxa de pCR. A análise estatística foi feita com Kaplan Meier, qui-quadrado de Pearson e o método de regressão de Cox.

Resultados: Registramos 156 pacientes entre 2006 e 2018. A taxa de DFS em 3 e 5 anos foi de 75% e 70%, respectivamente. A sobrevida global em 5 anos foi de 88%. A taxa de pCR foi de 12,8%. TRG 3 foi associado a um aumento na mortalidade, HR 3.148 (IC95%: 1,6-12,2, p<0,003) e uma diminuição na DFS, HR 3.148 (IC95%: 1,7-5,8, p<0,0001). O DFS de 5 anos com TRG 0,1, 2 e 3 foram 95%, 87%, 73,3% e 48%, respectivamente. Comparando o intervalo entre o final do tratamento de radioterapia e cirurgia de menos de 8 semanas versus 8 e 12 semanas versus acima de 12 semanas, as taxas de pCR foram 4,3%, 18,6% e 7,1% e as taxas de TRG 3 foram 32,6%, 18,6% e 57,1% (p<0,016), respectivamente.

Conclusão: Os resultados encontrados são favoráveis. O grau de regressão patológica do tumor é um importante fator prognóstico. O intervalo entre o tratamento neoadjuvante e a cirurgia parece influenciar o grau de regressão tumoral, sendo os melhores resultados da cirurgia observados quando realizada entre 8 e 12 semanas.

Keywords:

Rectal neoplasms - Neoadjuvant therapy - Antineoplastic agents - Radiotherapy

Descritores:

Neoplasias retais - Terapia neoadjuvante - Agentes antineoplásicos - Radioterapia

Publication History

Received: 06 April 2021

Accepted: 23 July 2021

Article published online:
18 February 2022

• REFERÊNCIAS

• 1 Ministério da Saúde (BR), Instituto Nacional de Câncer (INCA). Estimativa 2020: incidência de câncer no Brasil [Internet]. Rio de Janeiro: Ministério da Saúde/INCA; 2020. ;[access in 2021 Jul 4]. Available from: https://www.inca.gov.br/publicacoes/livros/estimativa-2020-incidencia-de-cancer-no-brasil
• 2 Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R. et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; Oct; 351 (17) 1731-1740
• 3 Hofheinz RD, Wenz F, Post S, Matzdorff A, Larchelt S, Hartmann JT. et al. Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial. Lancet Oncol 2012; Jun; 13 (06) 579-588
• 4 Sanghera P, Wong DW, McConkey CC, Geh JI, Hartley A. Chemoradiotherapy for rectal cancer: an updated analysis of factors affecting pathological response. Clin Oncol (R Coll Radiol) 2008; Mar; 20 (02) 176-183
• 5 Petrelli F, Sgroi G, Sarti E, Barni S. Increasing the interval between neoadjuvant chemoradiotherapy and surgery in rectal cancer: a meta-analysis of published studies. Ann Surg 2016; Mar; 263 (03) 458-464
• 6 Maas M, Nelemans PJ, Valentini V, Das P, Rödel C, Kuo LJ. et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010; Sep; 11 (09) 835-844
• 7 Rödel C, Martus P, Papadoupolos T, Füzesi L, Klimpfinger M, Fietkau R. et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 2005; Dec; 23 (34) 8688-8696
• 8 Ryan R, Gibbons D, Hyland JMP, Treanor D, White A, Mulcahy HE. et al. Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology 2005; Aug; 47 (02) 141-146
• 9 Vecchio FM, Valentini V, Minsky BD, Padula GDA, Venkatraman ES, Balducci M. et al. The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer. Int J Radiat Oncol Biol Phys 2005; Jul; 62 (03) 752-760
• 10 Wheeler JMD, Warren BF, Mortensen NJM, Ekanyaka N, Kulacoglu H, Jones AC. et al. Quantification of histologic regression of rectal cancer after irradiation: a proposal for a modified staging system. Dis Colon Rectum 2002; Aug; 45 (08) 1051-1056
• 11 Amin MB, Edge SB, Greene FL, Brookland DR, Washington RK, Gershenwald MK. et al. AJCC cancer staging manual. 8th. New York: Springer; 2017
• 12 Tang L, Berlin J, Branton LJ, Carter DK, Compton CC, Fitzgibbons P. et al. B. Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum [Internet]. Northfield: College of American Pathologist (CAP);; 2016. ; [access in 2016 Mar 23]. Available from: http://www.cap.org/ShowProperty?nodePath=/UCMCon/Contribution%20Folders/WebContent/pdf/cp-colon-16protocol-3400.pdf
• 13 Dossa F, Acuna SA, Rickles AS, Berho M, Wexner SD, Quereshy FA. et al. Association between adjuvant chemotherapy and overall survival in patients with rectal cancer and pathological complete response after neoadjuvant chemotherapy and resection. JAMA Oncol 2018; Jul; 4 (07) 930-937
• 14 Maas M, Nelemans PJ, Valentini V, Das P, Rödel C, Kuo LJ. et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010; Sep; 11 (09) 835-844
• 15 Hong YS, Kim SY, Lee JS, Nam BH, Kim JE, Kim KP. et al. Long-term results of the ADORE trial: adjuvant oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) versus 5-fluorouracil and leucovorin (FL) after preoperative chemoradiotherapy and surgery for locally advanced rectal cancer. J Clin Oncol 2018; 36 (Suppl 15): S3501
• 16 Fokas E, Liersch T, Fietkau R, Hohenberger W, Beissbarth T, Hess C. et al. Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: updated results of the CAO/ARO/AIO-94 trial. J Clin Oncol 2014; May; 32 (15) 1554-1562
• 17 Gouveia MC, Barbosa LER. Timing of neoadjuvant therapy and surgical treatment in rectal cancer. J Coloproctol (Rio J) 2019; Jun; 39 (02) 178-183
• 18 Bahadoer RR, Dijkstra EA, Van Etten B, Marijnen CAM, Putter H, Kranenbarg EMK. et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol 2021; Jan; 22 (01) 29-42
• 19 Conroy T, Bosset JF, Etienne PL, Rio E, François É, Mesgouez-Nebout N. et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2021; May; 22 (05) 702-715
• 20 Cercek A, Roxburgh CSD, Strombom P, Smith JJ, Temple LKF, Nash GM. et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol 2018; Jun; 4 (06) e180071